The following publications are relevant for describing the state of the art in the field of the invention:
1. Arévalo-Martin A, García-Ovejero D, Gómez O, Rubio-Araiz A, Navarro-Galve B, Guaza C, Molina-Holgado E, Molina-Holgado F. CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies. Br J. Pharmacol. 153, 216-25 (2008).
2. Avraham Y, Israeli E, Gabbay E, Okun A, Zolotarev O, Silberman I, Ganzburg V, Dagon Y, Magen I, Vorobia L, Pappo O, Mechoulam R, Ilan Y, Berry E M. Endocannabinoids affect neurological and cognitive function in thioacetamide—induced hepatic encephalopathy. Neurobiol. Disease, 21, 237-245 (2006).
3. Ashton J C, Glass M. The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Current Neuropharmacol. 5, 73-80 (2007).
4. Ashton J C, Rahman R M, Nair S M, Sutherland B A, Glass M, Appleton I. Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain. Neurosci Lett. 412, 114-7 (2007).
5. Bartlett, P D, Knox, L H. Org. Synth. Coll. Vol. 5, 689 (1973).
6. Benito C, Tolon R M, Pazos M R, NORez E, Castillo A I, Romero J. Cannabinoid CB2 receptors in human brain inflammation. Brit. J. Pharmacol. 153, 277-285 (2008).
7. Bilsland L G, Dick J R, Pryce G, Petrosino S, Di Marzo V, Baker D, Greensmith L. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD I mice. FASEB J. 20, 1003-5 (2006).
8. Centonze D, Rossi S, Finazzi-Agró A, Bernardi G, Maccarrone M. The (endo)cannabinoid system in multiple sclerosis and amyotrophic lateral sclerosis. Int Rev Neurobiol. 82, 171-86 (2007).
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10. Dagon Y, Avraham Y, Ilan Y, Mechoulam R, Berry E M. Cannabinoids ameliorate cerebral disfunction following liver failure via AMP-activated protein kinase. FASEB J. 21, 2431-2441 (2007).
11. Docagne F, Mestre L, Loría F, Hernangómez M, Correa F, Guaza C. Therapeutic potential of CB2 targeting in multiple sclerosis. Expert Opin Ther Targets. 12, 185-95 (2008).
12. Dominianni S J, Ryan, C W, DeArmitt C W. Synthesis of 5-(tert-alkyl)resorcinols. J. Org. Chem. 42, 344-346 (1977).
13. Fernandez-Ruiz J, Gonzalez S, Romero J, Ramos J A, Cannabinoids in neurodegeneration and neuroprotection. In R. Mechoulam (Ed.) “Cannabinoids as Therapeutics”. Birkhauser, Basel, 2005, pp 79-109.
14. Fernández-Ruiz J, Pazos M R, García-Arencibia M, Sagredo O, Ramos J A. Role of CB2 receptors in neuroprotective effects of cannabinoids, Mol. Cell. Endocrin. 286 (Suppl 1), S91-S96 (2008).
15. Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D M, Horowitz M, Pertwee R G, Ross R A, Mechoulam R, Fride E. HU-308: A specific agonist for CB2, a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. (US), 96, 14228-14233 (1999).
16. Hanus L O, Tchilibon S, Ponde D E, Breuer A, Fride E, Mechoulam R. Enantiomeric cannabidiol derivatives: Synthesis and binding to cannabinoid receptors. Org. Biomol. Chem. 3, 1116-1123 (2005).
17. Hertzog D L. Recent advances in the cannabinoids. Expert Opin. Ther. Patents, 14, 1435-1452 (2004).
18. Klegeris A, Bissonnette C J, McGeer P L. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor Br J. Pharmacol. 139, 775-86 (2003).
19. Kogan N M, Mechoulam R. The chemistry of endocannabinoids. J. Endocrinol. Investig. 29 (Suppl. 3) 3-14 (2006).
20. Kogan, N M, Mechoulam, R. Cannabinoids in health and disease. Dialogues Clin. Neurosci. 9, 413-430 (2007).
21. Lotersztajn S, Teixeira-Clerc F, Julien B, Deveaux V, Ichigotani Y, Manin S, Tran-Van-Nhieu J, Karsak M, Zimmer A, Mallat A. CB2 receptors as new therapeutic targets for liver diseases. Brit. J. Pharmacol., 153, 286-289 (2008).
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25. Ofek O, Karsak, M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I. Peripheral CB2 cannabinoid receptor regulates bone mass. Proc. Natl. Acad. Sci., Proc. Natl. Acad. Sci. (US) 103, 696-701 (2006).
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27. Palazuelos J, Aquado T, Egia A, Mechoulam R, Guzman M, Galve-Roperh I. Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J. 580, 4337-4345 (2006).
28. Palazuelos J, Davoust N, Julien B, Hatterer E, Aguado T, Mechoulam R, Benito C, Romero J, Silva A, Guzman M, Nataf S, Galve-Roperh I. The CB2 cannabinoid receptor controls myeloid progenitor trafficking. Involvement in the pathogenesis of an animal model of multiple sclerosis. J Biol. Chem. 283, 13320-13329 (2008).
29. Steffens S, Mach F. Cannabinoid receptors in atherosclerosis. Curr. Opinion Lipidology, 17, 519-526, 2006.
30. Steffens S, Veillard N R, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard J L, Mach F. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434, 782-786 (2005).
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32. van Sickle M D, Duncan M, Kingsley P J, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison J S, Marnett L J, Di Marzo V, Pittman Q J, Patel K D, Sharkey K A. Identification and functional characterization of brain stem cannabinoid CB2 receptors. Science, 310, 329-332 (2005).
33. Yamamoto W, Mikami T, Iwamura H. Involvement of central cannabinoid CB2 receptor in reducing mechanical allodynia in a mouse model of neuropathic pain. Eur. J. Pharmacol. 583, 56-61 (2008).
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35. Pertwee R G, Gibson T M, Stevenson L A, Ross R A, Banner W K, Saha B, Razdan R K and Martin B R. 0-1057, a potent water-soluble cannabinoid receptor agonist with antinociceptive properties. Br J. Pharmacol. 129, 1577-1584 (2000).
36. Shohami E, Gallily R, Mechoulam R, Bass R and Ben-Hur T. Cytokine production in the brain following closed head injury: dexanabinol_HU-211/is a novel TNF-α inhibitor and an effective neuroprotectant. J. Neuroimmunol. 72, 169-177 (1997).
37. Ross R A, Brockie H C, Stevenson L A, Murphy V L, Templeton F, Makriyannis A and Pertwee R G. Agonist-inverse agonist characterization at CB 1 and CB2 cannabinoid receptors of L759633, L759656 and AM630. Br J. Pharmacol. 126, 665-672 (1999).
38. Beni-Adani L, Gozes I, Cohen Y, Assaf Y, Steingart R A, Brenneman D E, Eizenberg O, Trembolver V and Shohami E. A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J Pharmacol Exp Ther. 296, 57-63 (2001).
Two cannabinoid receptors have been well characterized so far—the CB 1 receptor, which is present mainly in the central nervous system (CNS), (and to a lesser extent in the periphery), and the CB2 receptor which is considered mainly a peripheral receptor. Natural stimulation of the CB1 receptor, which is produced by the endogenous cannabinoids, when and where needed, is central to many of our physiological systems. However exogenous administration of CB1 agonists (such as the marijuana constituent THC) may lead to undesirable side effects. Therefore CB1 agonists, which act on the central nervous system, are of limited therapeutic value (for a recent review see Kogan and Mechoulam, 2007).
The CB2 receptor is present in low levels in the CNS, mainly in glial cells. However, numerous neurological conditions have been shown to induce expression of this receptor in the brain. Some of these conditions are cerebral hypoxia-ischemia, cerebral artery occlusion, Alzheimer's disease and Huntington's disease. It was further shown that stimulation of the CB2 receptor is not accompanied by undesirable CNS or other effects, such as major and/or detrimental psychoactive effects, usually associated with the stimulation of the CB1 receptor (Ashton and Glass, 2007).
There is therefore a need for selective CB2 receptor stimulants, capable of being utilized for treating diseases, disorders or conditions associated with, or benefiting from such stimulation of CB2 receptors.